Paste formulations

ABSTRACT

This invention provides for a pharmaceutical or veterinary paste formulation comprising: an effective amount of a therapeutic agent; fumed silica; a viscosity modifier; a hydrophilic carrier; optionally, an absorbent; and optionally, a colorant, stabilizer, surfactant, or preservative. This invention also provides for methods of using these formulations for treating various disease states as well.

[0001] The invention relates to a new crystalline form of3-(cyclopropylmethoxy)-4-[4-(methylsulfonyl)phenyl]-5,5-dimethyl-5H-furan-2-one,herein designated as “Polymorphic Form B or Polymorph B”, withpharmaceutically acceptable bases, which are inhibitors ofcyclooxygenase-2 and useful as non-steroidal antiinflammatory drugs.

[0002] In another aspect, the invention relates to pharmaceuticalcompositions and methods of making and using the Polymorph B of3-(cyclopropylmethoxy)-4-[4-(methylsulfonyl)phenyl]-5,5-dimethyl-5H-furan-2-one.

[0003] The invention also relates to a method for preparing polymorphicForm B comprising agitating polymorphic Form A in the presence ofmethanol.

[0004] The invention also relates to a method for preparing polymorphicForm B comprising agitating polymorphic Form A in the presence ofpolymorphic Form B seeds in methanol.

[0005] Non-steroidal antiinflammatory drugs exert most of theirantiinflammatory, analgesic and antipyretic activity and inhibithormone-induced uterine contractions and certain types of cancer growththrough inhibition of prostaglandin G/H synthase, also known ascyclooxygenase.

[0006] Two forms of cyclooxygenase are known, corresponding tocyclooxygenase-1 (COX-1) or the constitutive enzyme, as originallyidentified in bovine seminal vesicles, and a second inducible form ofcyclooxygenase, cyclooxygenase-2 (COX-2) which has been cloned,sequenced and characterized initially from chicken, murine and human andanimal sources. This enzyme is distinct from the COX-1 which has beencloned, sequenced and characterized from various sources including thesheep, the mouse and man. The second form of cyclooxygenase, COX-2, israpidly and readily inducible by a number of agents including mitogens,endotoxin, hormones, cytokinos and growth factors. As prostaglandinshave both physiological and pathological roles, it was concluded thatthe constitutive enzyme, COX-1, is responsible, in large part, forendogenous basal release of prostaglandins and hence is important intheir physiological functions such as the maintenance ofgastrointestinal integrity and renal blood flow. In contrast, it wasconcluded that the inducible form, COX-2 is mainly responsible for thepathological effects of prostaglandins where rapid induction of theenzyme would occur in response to such agents as inflammatory agents,hormones, growth factors, and cytokines. Thus, a selective inhibitor ofCOX-2 will have similar antiinflammatory, antipyretic and analgesicproperties to a conventional non-steroidal antiinflammatory drug, and inaddition would inhibit hormone-induced uterine contractions and havepotential anti-cancer and anti-angiogenic effects, but will have adiminished ability to induce some of the mechanism-based side effects.In particular, such a compound should have a reduced potential forgastrointestinal toxicity, a reduced potential for renal side effectsand a reduced effect on bleeding times and possibly a lessened abilityto induce asthma attacks in aspirin-sensitive asthmatic subjects.

[0007] Furthermore, such a compound will also inhibit prostanoid-inducedsmooth muscle contraction by preventing the synthesis of contractileprostanoids and hence may be of use in the treatment of prematurelabour, asthma and eosinophil related disorders. It will also be of usein the treatment of Alzheimer's disease, for decreasing bone lossparticularly in postmenopausal women (i.e. treatment of osteoporosis)and for the treatment of glaucoma. It may also be useful for thetreatment of age-related dementia, for decreasing osteoclastic bone lossand for treatment of glaucoma A brief description of the potentialutility of cyclooxygenase-2 inhibitors is given in an article by JohnVane, Nature, Vol. 367, pp. 215-216, 1994, and in an article in DrugNews and Perspectives, Vol. 7, pp. 501-512, 1994.

[0008] Compounds having a potent COX-2 inhibitory effect are disclosedin WO 97/44027, WO 97/28121, WO 98/41516, WO 97/16435 and WO 97/14691.

[0009] WO 97/14691 discloses methylsulfonylphenyl-5H-furan-2-onecompounds which are potent COX-2 inhibitors, namely3-(cyclopropylmethoxy)-4-[4-(methylsulfonyl)phenyl]-5,5-dimethyl-5H-furan-2-onewhich was isolated in a crystalline form which is herein designated as“Polymorphic Form A or Polymorph A”.

[0010] The formula of 3-(cyclopropylmethoxy)-4-[4-(methylsulfonyl)phenyl]-5,5-dimethyl-5H-furan-2-one is the following.

[0011] Recrystallization of polymorph A for purification purposes leadedto solubility problems in methyltertiobutylether.

[0012] Mixtures of3-(cyclopropylmethoxy)-4-(4-methylsulfonyl)phenyl-5,5-dimethylfuranonesolid at 6.3% weight in methyltertiobutylether could no longer besolubilised. After dilution and recrystallization, the powder obtainedwas analysed by X-Ray diffraction and showed a different pattern thanthe initial product.

[0013] The experiment was reproduced in several solvents such asmethanol and dimethylformamide. The new solid form obtained was namedpolymorph B.

[0014] In a first embodiment the invention provides3-(cyclopropylmethoxy)-4-[4-(methylsulfonyl)phenyl]-5,5-dimethyl-5H-furan-2-onein Polymorphic Form B, which is useful as a “non steroidalantiinflammatory agent” for the treatment of cyclooxygenase-2 mediateddiseases.

[0015] Polymorph B possesses better flow characteristics than PolymorphA and is thermodynamically more stable than Polymorph A. Thus, PolymorphB is easier to handle (remove from vessel and transfer to filter),filter and dry than Polymorph A. Polymorph B is also easier to feed andmicronize. Hence, the methods for its manufacture are more easilyvalidated than that of Polymorph A.

[0016] Polymorph B may be characterized by its powder X-ray diffractionpattern hereinafter described in greater detail with respect to theenclosed figures.

BRIEF DESCRIPTION OF THE FIGURES

[0017]FIG. 1 shows the XRPD pattern of form A

[0018]FIG. 2 shows the XRPD pattern of form B

[0019]FIG. 3 shows the habit pattern of form A

[0020]FIG. 4 shows the habit pattern of form B

[0021]FIG. 5 is the DSC curve of a form A product heated at 40° C./mn

[0022]FIG. 6 is the DSC curve of a form A product heated at 2° C./mn

[0023]FIG. 7 shows the X-Ray diffraction patterns at 30° C., −10°, 80,90, 100, 110, 120 and 130° C. with form A at 30° C. and form B appearingat 80° C. At 130° C., there is no signal as all the product is melted.

[0024]FIG. 8 represents the X-ray diffraction pattern of the initialreaction medium used for converting Polymorph A to Polymorph B withoutseeding.

[0025]FIG. 9 represents the X-ray diffraction pattern of the endreaction medium used for converting Polymorph A to Polymorph B.

[0026]FIG. 10 represents the X-ray diffraction pattern of the initialreaction medium used for converting Polymorph A to Polymorph B withseeding.

[0027]FIG. 11 represents the X-ray diffraction pattern of the endreaction medium used for converting Polymorph A to Polymorph B withseeding.

POWDER X-RAY DIFFRACTION

[0028] The powder X-ray diffraction pattern of Polymorph A and PolymorphB was obtained by completely and uniformly filling the sample holder ofthe SIEMENS D5000 with the sample utilizing a spatula. The sample wasthen irradiated with the SIEMENS D5000 under the conditions described inTable I. TABLE 1 Parameters for powder X-Ray Diffraction InstrumentSiemens D5000 X-Ray Target Copper (d = 1,54 Å) Voltage 40 kV Current 30mA Detector Scintillator Two-theta range 3°-60° Scar Type continuousChopper Increment 0,01° Beam Slit 0,5° Receiving beam scatter slit 0,5°Receiving detector slit 6 mm Atmosphere Air

[0029] The X-ray powder diffraction pattern of the micronized form ofPolymorph A and B are represented respectively in FIGS. 1 and 2.

Handling Properties

[0030] It has been discovered that the new polymorphic form B has moreadvantageous handling properties in the micronization or preparation ofpharmaceutical compositions.

[0031] After crystallization and before micronization, the Carr Index ofB form is lower than 10 (in %). The Carr Index Cl is defined as:${Cl} = \frac{P - L}{P}$

[0032] where P is the packed bulk density (g cm⁻³), L is the loose bulkdensity (g cm⁻³). Cl is also know as a compressibility index. A lowfigure for Cl corresponds to a high degree of flowability.

[0033] The Carr Index way be calculated from Mercury IntrusionPorosimetry or measured by Tap-Tap.

[0034] Examples of Carr Index for unmilled products are given in table2. TABLE 2 Polymorphic form Crystallisation Process Carr Index A Labscale 26 to 27 A Pilot scale 29 to 33 B Recrystallisation in  2 to 3MTBE Lab scale B Recrystallisation in  2 to 4 MTBE Pilot scale

[0035] These better handling properties are due to:

[0036] bigger crystals (before micronization),

[0037] a more regular shape.

[0038] Form A is made of needle-like crystals (FIG. 3) when form B ismode of big faceted crystals (FIG. 4).

DSC (Differential Scanning Calorimetry)

[0039] When heated, form A transforms to form B depending on the heatingrate.

[0040] For instance, when the heating rate is 40° C./mn, the DSC curveshows (FIG. 5):

[0041] an endothermal peak around 90-100° C. due to melting of A form,

[0042] an exothermal peak corresponding to the transition A→B,

[0043] an endothermal peak around 120° C. due to melting of B form,

[0044]  when the heating rate is 2° C./mn (FIG. 6) the DSC curve shows:

[0045] a very small exothermal peak corresponding to the transition A→B,

[0046] an endothermal peak due to melting of B form.

[0047] Therefore, the transition A→B is under kinetic control as usualin case of polymorphism. The transition from A to B may also be followedby X-Ray under heating (FIG. 7).

[0048] According to Burger's rule (“On the Polymorphism ofPharmaceuticals an Other Molecular Crystals”—Theory of ThermodynamicRules; A. BURGER—R; RAMBERGER—Mikrochimica Ada 1979; II, 259-271), thesystem is monotropic, and the B form is the most stable form.

[0049] In a second embodiment, the invention encompasses pharmaceuticalcompositions for inhibiting cyclooxygenase and for treatingcyclooxygenase mediated diseases as disclosed herein comprising apharmaceutically acceptable carrier and a non-toxic therapeuticallyeffective amount of Polymorph B.

[0050] Within this embodiment the invention encompasses pharmaceuticalcompositions for inhibiting cyclooxygenase-2 and for treatingcyclooxygenase-2 mediated diseases as disclosed herein comprising apharmaceutically acceptable carrier and a non-toxic therapeuticallyeffective amount of Polymorph B.

[0051] In a third embodiment, the invention encompasses a method ofinhibiting cyclooxygenase and treating cyclooxygenase mediated diseases,advantageously treated by an active agent that selectively inhibitsCOX-2 in preference to COX-1 as disclosed herein comprising:administration to a human or animal in need of such treatment of anon-toxic therapeutically effective amount of a compound of Formula I asdisclosed herein.

[0052] The pharmaceutical compositions of the present invention comprisePolymorph B as an active ingredient, and may also contain apharmaceutically acceptable carrier and optionally other therapeuticingredients.

[0053] Polymorph B is useful for the relief of pain, fever andinflammation of a variety of conditions including signs associated withbacterial and viral infections, sprains and strains, tendonitis,myositis, neuralgia, synovitis, arthritis, including rheumatoid andosteoarthritis, ankylosing spondylitis, bursitis, colic gastroenteritis,colitis, cystitis, ophthalmitis, burns and injuries, and followingsurgical and dental procedures. In addition, such a compound may inhibitcellular neoplastic transformations and metastic tumor growth and hencecan be used in the treatment of cancer. Polymorph B may also be of usein the treatment and/or prevention of cyclooxygenase-mediatedproliferative disorders such as may occur in diabetic retinopathy andtumour angiogenesis.

[0054] Polymorph B will also inhibit prostanoid-induced smooth musclecontraction by preventing the synthesis of contractile prostanoids andhence may be of use in the treatment of premature labor, asthma andeosinophil related disorders. It will also be of use in the treatment ofage-related dementia, and for the prevention of bone loss (treatment ofosteoporosis) and for the treatment of glaucoma.

[0055] By virtue of its high cyclooxygenase-2 (COX-2) activity and/orits specificity for cyclooxygenase-2 over cyclooxygenase-1 (COX-1),Polymorph B will prove useful as an alternative to conventionalnon-steroidal antiinflammatory drugs (NSAID'S) particularly where suchnon-steroidal antiinflammatory drugs may be contra-indicated such as inpatients with peptic ulcers, gastritis, regional enteritis, ulcerativecolitis, diverticulitis or with a recurrent history of gastrointestinallesions; GI bleeding, coagulation disorders including anemia such ashypoprothrombinemia, haemophilia or other bleeding problems; kidneydisease; those prior to surgery or taking anticoagulants.

[0056] Similarly, Polymorph B, will be useful as a partial or completesubstitute for conventional NSAID'S in preparations wherein they arepresently co-administered with other agents or ingredients.

[0057] Thus in further aspects, the invention encompasses pharmaceuticalcompositions for treating cyclooxygenase-2 mediated diseases as definedabove comprising a non-toxic therapeutically effective amount ofPolymorph B and one or more ingredients such as another pain relieverincluding acetominophen or phanacetin; a potentiator includingacetominophen or phenacetin; a potentiator including caffeine; anH₂-antagonist, aluminum or magnesium hydroxide, simethicone, adecongestant including phenylephrine, phenylpropanolamine,pseudophedrine, oxymetalozine, ephinephrine, naphazoline,xylometazoline, propylhexedrine, or levodesoxyephedrine, an antiitussiveincluding codeine, hydrocodone, caramiphen, carbetapentane, ordextramethorphan; a prostaglandin including misoprostol, enprostil,rioprostil, ornoprostol or rosaprostol; a diuretic; a sedating ornon-sedating antihistamine.

[0058] In addition the invention encompasses a method of treatingcyclooxygenase mediated diseases comprising: administration to a patientin need of such treatment a non-toxic therapeutically effective amountof Polymorph B, optionally co-administered with one or more of suchingredients as listed immediately above.

[0059] For the treatment of any of these cyclooxygenase mediateddiseases Polymorph B may be administered orally, topically,parenterally, by inhalation spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattlesheep, dogs, cats, etc., the compound of the invention is effective inthe treatment of humans.

[0060] As indicated above, pharmaceutical compositions for treatingcyclooxygenase-2 mediated diseases as defined may optionally include oneor more ingredients as listed above.

[0061] The pharmaceutical compositions containing the active ingredientmay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily solutions, aqueous or oilysuspensions, dispersible powders or granules, emulsions, hard or softcapsules, or syrups or elixirs. Compositions intended for oral use maybe prepared according to any method known to the art for the manufactureof pharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets.

[0062] These excipients may be, for example, inert diluents, such ascalcium carbonate, sodium carbonate, lactose, calcium phosphate orsodium phosphate; granulating and disintegrating agents, for example,corn starch, or alginic acid; binding agents, for example starch,gelatin or acacia, and lubrificating agents, for example, magnesiumstearate, stearic acid or talc. the tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the technique described in the U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlrelease.

[0063] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredients is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredients is mixed withwater or miscible solvents such as propylene glycol, PEGs and ethanol,or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0064] Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occuring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

[0065] Oily suspensions may be formulated by suspending the activeingredient in a vegetable oil, for example, arachis oil, olive oil,sesame oil or coconut oil, or in mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for example,beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavoring agents may be added to provide apalatable oral preparation. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

[0066] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example, sweetening, flavoring andcoloring agents, may also be present.

[0067] The pharmaceutical compositions of the invention may also be inthe form of an oil-in-water emulsions. The oily phase may be a vegetableoil, for example, olive oil or arachis oil, or a mineral oil, forexample, liquid paraffin or mixtures of these. Suitable emulsifyingagents may be naturally-occurring phosphatides, for example, soy bean,lecithin, and esters or partial esters derived from fatty acids andhexitol anhydrides, for example, sorbitan monoleate, and condensationproducts of the said partial esters with ethylene oxide, for example,polyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavouring agents.

[0068] Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleagenous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-aceptable diluent or solvent, for example, as a solution in1,3-butane diol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. Cosolvents such as ethanol, propylene glycol or polyethyleneglycols may also be used. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

[0069] Polymorph B may also be administered in the form of asuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

[0070] For oral or topical use, creams, ointments, gels, solutions,pastes, suspensions, etc., containing the compound of Formula I areemployed. (For purposes of this application, topical application shallinclude mouth washes and gargles). Topical formulations may generally becomprised of a pharmaceutical carrier, cosolvent, emulsifier,penetration enhancer, preservative system, and emollient.

[0071] Dosage levels of the order of from about 0.01 mg to about 140mg/kg of body weight per day are useful in the treatment of theabove-indicated conditions, or alternatively about 0.5 mg to about 7 gper patient per day. For example, inflammation may be effectivelytreated by the administration of from about 0.01 to 50 mg of thecompound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5 g per patient per day.

[0072] The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Forexample, a formulation intended for the oral administration of animalsmay contain from 0.5 mg to 5 g of active agent compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95 percent of the total composition. Dosage unitforms will generally contain between from about 1 mg to about 500 mg ofan active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg,400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

[0073] It will be understood, however, that the specific dose level forany particular patient will depend upon a variety of factors includingthe age, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

[0074] Examples for the preparation of Polymorph B are providedhereunder.

[0075] The synthesis of Polymorph A of3-(cyclopropylmethoxy)-4-[4-(methylsulfonyl)phenyl]-5,5-dimethyl-5H-furan-2-oneis disclosed in WO 97/14691 (Example 148).

EXAMPLE 1

[0076] Conversion of Polymorph A to Polymorph B by Stirring in MethanolWithout Seeding

[0077] To a 5 ml flask was added 1 g of methanol and 1.5 g of polymorphA.

[0078] The agitation was maintained at room temperature for 50 minutes.All polymorph A had converted to polymorph B after this time. Theresults on the polymorphic form were confirmed by X-Ray diffraction(FIG. 9)

EXAMPLE 2 Conversion of Polymorph A to Polymorph B by Stirring inMethanol a 50/50 Mixture of the Two Solids

[0079] To a 5 ml flask was added 2.85 g of methanol, 0.95 g of polymorphA and 0.95 g of polymorph B

[0080] The agitation was maintained at room temperature for 50 minutes.All polymorph A had converted to polymorph B after this time. Theresults on the polymorphic form were confirmed by X-Ray diffraction(FIGS. 10 and 11)

EXAMPLE 3 Recrystallization of Polymorph A to Polymorph B from a 30%Weight Solution in Methylcyclohexan/tetrahyfrofuran (30/70 w/w) Seededwith Polymorph B

[0081] To a 500 ml flask was added 154 g of polymorph A, 252 g oftetrahydrofuran and 108 g of methylcyclohexan. The mixture was heated at60° C. The batch was in total solution at 58° C.

[0082] It was cooled to 48° C. over 10 min. and seeded with polymorph B.Immediate crystallization was observed. The batch was cooled at −13° C.over 30 min., filtered and dried at 70° C. under vacuum.

[0083] 145.1 g of solid was isolated. The results on the polymorphicform were confirmed by X-Ray diffraction to be polymorph B.

EXAMPLE b 4 Recrystallization of Polymorph A to Polymorph B byPrecipitation Process in Methylcyclohexan/tetrahyfrofuran (30/70 w/w)Seeded with Polymorph B

[0084] To a 1 I flask was added 153 g of polymorph A and 179 g oftetrahydrofuran. The mixture was heated at 50° C. The batch was in totalsolution at 50° C. The solution is added to a 1 I flask containing 170 gof methylcyclohexan at 0° C. seeded with polymorph B in suspension.Immediate crystallization was observed. During the addition, medium ismaintain at 0° C. and aged 60 min. after addition end. The batch is thenfiltered and dried at 70° C. under vacuum. 144.9 g of dried solid isobtained. The results on the polymorphic form were confirmed by IRanalysis to be polymorph B

What is claimed is:
 1. A pharmaceutical or veterinary paste formulationcomprising: (a) an effective amount of a therapeutic agent; (b) fumedsilica; (c) a viscosity modifier; (d) a carrier; (e) optionally, anabsorbent; and (f) optionally, a colorant, stabilizer, surfactant, orpreservative.
 2. The paste according to claim 1, which comprises: (a) atherapeutic agent selected from the group consisting of insecticides,acaricides, parasiticides, antibiotics. growth enhancers, or oil-solubleNSAIDS; (b) fumed silica; (c) a viscosity modifier; (d) an absorbent;(e) a colorant; and (f) a carrier which is triacetin, a monoglyceride, adiglyceride, or a triglyceride.
 3. The paste formulation according toclaim 3, wherein the viscosity modifier is PEG 200, PEG 300, PEG 400,PEG 600, monoethanolamine, triethanolamine, glycerol, propylene glycol,polyoxylene sorbitan monoleate, or poloxamers; the absorbent ismagnesium carbonate, calcium carbonate, starch, or cellulose and itsderivatives; and the colorant is titanium dioxide, dye or lake.
 4. Thepaste formulation according to claim 1, comprising: (a) a therapeuticagent selected from the group consisting of avermectins, milbemycins,nordulisporic acid and its derivatives, estrogens, progestins,androgens, substituted pyridyl methyl derivatives, phenylpyrazoles,COX-2 inhibitors or a proton pump inhibitor. (b) fumed silica; (c) aviscosity modifier; (d) an absorbent; (e) a colorant; and (f) a carrierwhich is triacetin, a monoglyceride, a diglyceride, or a triglyceride.5. The paste formulation according to claim 4, wherein the viscositymodifier is PEG 200, PEG 300, PEG 400, PEG 600, monoethanolamine,triethanolamine, glycerol, propylene glycol, polyoxyethylene sorbitonmonoleate, or poloxamers; the absorbent is magnesium carbonate, calciumcarbonate, starch, or cellulose and its derivatives; and the colorant istitanium dioxide, dye or lake.
 6. The paste formulation according toclaim 1, which, based upon total weight of composition, comprises: (a)about 0.01 to about 50% of a therapeutic agent; (b) about 0.02 to about20% fumed silica; (c) about 0.01% to about 20% of a viscosity modifier;(d) 0% to about 30% of an absorbent; (e) 0% to about 20% of a colorant;and (f) Q.S. a carrier.
 7. The paste formulation according to claim 4,based upon total weight of the composition, comprises: (a) about 0.01 toabout 50% of a therapeutic agent; (b) about 1% to about 6.5% fumedsilica; (c) about 0.05% to about 5% of a viscosity modifier; (d) about1% to about 10% of an absorbent; (e) 0.01% to about 10% of a colorant;and (f) Q.S. a carrier.
 8. The paste formulation according to claim 4,wherein the therapeutic agent is an avermectin or a milbemycin.
 9. Thepaste formulation according to claim 8, wherein the avermectin ormilbemycin is ivermectin, praziquantel, abamectin, ememectin,eprinomectin, doramectin, moxidectin, or selamectin.
 10. The pasteformulation according to claim 5, wherein the therapeutic agent ispraziquantel or selamectin.
 11. The paste formulation according to claim5, wherein the therapeutic agent is a COX-2 inhibitor.
 12. The pasteformulation according to claim 11, wherein the COX-2 inhibitor is3-(cyclopropylmethoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-5H-furan-2-oneor3-(cyclopropylethoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-5H-furan-2-oneor pharmaceutically acceptable salts or hydrates of these compounds. 13.The paste formulation according to claim 12, wherein the COX-2 inhibitoris the polymorphic B form of3-(cyclopropylmethoxy)-4-[4-(methylsulfonyl)phenyl-5,5-dimethyl]-5H-furan-2-one.14. The paste formulation according to claim 5, wherein the therapeuticagent is a substituted pyridylmethyl derivative or a phenylpyrazole. 15.The paste formulation according to claim 14, wherein the therapeuticagent is imidacloprid or fipronil.
 16. The paste formulation accordingto claim 3, wherein the therapeutic agent NSAID.
 17. The pasteformulation according to claim 16, wherein the therapeutic agent iscarprofen, flunixin, ketoprofen, meloxicam, naproxen or phenylbutazone.18. The paste formulation according to claim 5, wherein the therapeuticagent is a proton pump inhibitor.
 19. The paste formulation according toclaim 18, wherein the proton pump inhibitor is omeprazole or a saltthereof.
 20. The paste formulation according to claim 5, wherein thetherapeutic agent is an estrogen, a progenstin, or an androgen.
 21. Thepaste formulation according to claim 1, wherein the therapeutic agent isan insect growth regulator.
 22. The paste formulation according to claim4, which, based upon total weight of the composition, comprises: (a)2.5% of a therapeutic agent; (b) 4.0% fumed silica; (c) 1.0%monoethanolamine; (d) 1.0% titanium dioxide; (e) 50.0% triacetin; (f)41.5% propylene glycolcaprlic-capric diester
 840. 23. The pasteformulation according to claim 4, which, based upon total weight of thecomposition, comprises: (a) 0.82% of a therapeutic agent; (b) 4.25%fumed silica; (c) 2.0% magnesium carbonate; (d) 0.20% titanium dioxide;(e) 0.4% polyethylene glycol 300; and (f) 92.33% triacetin.
 24. Thepaste formulation according to claim 1, wherein the formulation is fororal administration.
 25. The paste formulation according to claim 1,wherein the formulation is for topical, dermal or transdermaladministration.
 26. The paste formulation according to claim 1, whichcomprises an antioxidant and the antioxidant is selected from the groupconsisting of alpha tocopherol, ascorbic acid, ascrobyl palmitate,fumeric acid, malic acid, sodium ascorbate, sodium metobisulfate,n-propyl gallate, BHA, BHT and monothioglycerol.
 27. The pasteformulation according to claim 1 which comprises a preservative and thepreservative and the preservative is selected from the group consistingof the parabens, benzalkonium chloride, benzethonium chloride, benzoicacid, benzyl alcohol, bronopol, cetrimide, chlorhexidine, chlorobutanol,chlorocresol, cresol, imidurea, phenol, phenoxyethanol, phenylethylalcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuricnitrate, potassium sorbate, sodium benzoate, sodium propionate, sorbicacid, and thimerosal.
 28. A method for treating inflammation, pain, orfever which comprises administering of administering an effective amountof a paste formulation according to claim 16 to a host in need thereof.29. The method according to claim 28, wherein the host is a horse,cattle, pig or human.
 30. A method for treating inflammation, pain orfever, rheumatoid arthritis or osteoarthritis which comprisesadministering an effective amount of a paste formulation according to11, to a host in need thereof.
 31. The method according to claim 30,wherein the host is a horse, cattle, pig or human.
 32. A method fortreating or preventing insect infestation which comprises administeringan effective amount of a paste formulation according to claim 14 to ahost in need thereof.
 33. The method according to claim 32, wherein theinsects are fleas.
 34. A method for treating or preventing parasiticinfestations in a host in need thereof, which comprises administering apaste formulation according to claim 8 to a host in need thereof. 35.The method according to claim 34, wherein the host is a horse, cattle,pig or human.
 36. A method for regulating fertility in a host in needthereof, which comprises administering a paste formulation according toclaim 20 to said host.
 37. The method according to claim 36, wherein thehost is a horse, cattle, pig or human.
 38. A method for killing insectswhich comprises applying to said insects or an environment they reside,an effective amount of a compound according to claim
 21. 39. A methodfor inhibiting acid secretion in the stomach of a host in need thereofwhich comprises administering to said host an effective amount of apaste according to claim
 18. 40. A method for preventing or treating abacterial infection of a host in need thereof which comprisesadministering to said host an effective amount of paste according toclaim
 18. 41. The paste formulation according to claim 3 wherein thetherapeutic agent is an antibiotic.
 42. The paste formulation accordingto claim 41, wherein the antibiotic is 8a-azalide, azithromycin orerythromycin.
 43. A method of treating bacterial infection in a host inneed thereof which comprises administering to said host an effectiveamount of a compound according to claim
 42. 44. A process for preparinga paste formulation according to claim 1, comprising the steps of: (a)dissolving or dispensing the therapeutic agent into the carrier bymixing; (b) adding the fumed silica to the hydrophobic carriercontaining the dissolved therapeutic agent and mixing until the silicais dispersed in the carrier; (a) allowing the intermediate formed in (b)to settle for a time sufficient in order to allow the air entrappedduring step (b) to escape; and (d) adding the viscosity modifier to theintermediate with mixing to produce a uniform past.